Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors.

Abstract

Three different membrane-type matrix metalloproteinases (MT1-, MT2-, and MT3-MMPs) are known to activate in vitro the zymogen of MMP-2 (pro-MMP-2, progelatinase A), which is one of the key MMPs in invasion and metastasis of various cancers. In the present study, we have examined production and activation of pro-MMP-2, expression of MT1-, MT2-, and MT3-MMPs and their correlation with pro-MMP-2 activation, and localization of MMP-2, MT1-MMP, and MT2-MMP in human astrocytic tumors. The sandwich enzyme immunoassay demonstrates that the production levels of pro-MMP-2 in the anaplastic astrocytomas and glioblastomas are significantly higher than that in the low-grade astrocytomas (P<0.05 and P<0.01, respectively), metastatic brain tumors (P<0.05), or normal brains (P<0.01). Gelatin zymography indicates that the pro-MMP-2 activation ratio is significantly higher in the glioblastomas than in other astrocytic tumors (P<0.01), metastatic brain tumors (P<0.01), and normal brains (P<0.01). The quantitative reverse transcription polymerase chain reaction analyses demonstrate that MT1-MMP and MT2-MMP are expressed predominantly in glioblastoma tissues (17/17 and 12/17 cases, respectively), and their expression levels increase significantly as tumor grade increases. MT3-MMP is detectable in both astrocytic tumor and normal brain tissues, but the mean expression level is approximately 50-fold lower compared with that of MT1-MMP and MT2-MMP in the glioblastomas. The activation ratio of pro-MMP-2 correlates directly with the expression levels of MT1-MMP and MT2-MMP but not MT3-MMP. In situ hybridization indicates that neoplastic astrocytes express MT1-MMP and MT2-MMP in the glioblastoma tissues (5/5 cases and 5/5 cases, respectively). Immunohistochemically, MT1-MMP and MT2-MMP are localized to the neoplastic astrocytes in glioblastoma samples (17/17 cases and 12/17 cases, respectively), which are also positive for MMP-2. In situ zymography shows gelatinolytic activity in the glioblastoma tissues but not in the normal brain tissues. These results suggest that both MT1-MMP and MT2-MMP play a key role in the activation of pro-MMP-2 in the human malignant astrocytic tumors and that the gelatinolytic activity is involved in the astrocytic tumor invasion.

• Authors: M Nakada, H Nakamura, E Ikeda, N Fujimoto, J Yamashita, H Sato, M Seiki, Y Okada
• Journal: The American journal of pathology (Am J Pathol) Vol. 154 Issue 2 Pg. 417-28 (Feb 1999) ISSN: 0002-9440 [Print] United States
• PMID: 10027400 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Enzyme Precursors
• RNA, Messenger
• Collagenases
• Gelatinases
• Metalloendopeptidases
• progelatinase
• Matrix Metalloproteinase 3
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 1

Topics

• Adenocarcinoma (secondary)
• Astrocytoma (enzymology, pathology)
• Brain Neoplasms (enzymology, secondary)
• Collagenases (genetics, metabolism)
• DNA Primers (chemistry)
• Enzyme Precursors (genetics, metabolism)
• Gelatinases (genetics, metabolism)
• Glioblastoma (enzymology, pathology)
• Humans
• Immunoenzyme Techniques
• In Situ Hybridization
• Lung Neoplasms (pathology)
• Matrix Metalloproteinase 1
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 3 (genetics, metabolism)
• Metalloendopeptidases (genetics, metabolism)
• RNA, Messenger (biosynthesis)
• Reverse Transcriptase Polymerase Chain Reaction